NanoViricides Inc. (NNVC)

[robi-1-kenobi]

TASKS resulting in RangeFinding Toxicity 18mo after preIND meeting

There are good reasons for conservative timelines to start the formal Range Finding Toxicity study after the pre-IND meeting.

The design of the drug may have been optimized and finalized at the time of the pre-IND, but the consistency of the manufactured materials with the various processes would not have been.

The 3 scales of manufacturing processes below need to have similar CMC with respect to specifications and characterization of the product output.
1. Lab scale for formal Range Finding Toxicity Study
2. Larger lab scale for GLP Regulatory Toxicity study, PK and PD studies
3. Commercial scale to manufacture cGMP product for human clinical studies.

All potential specifications and characterizations of the test materials need to be consistent across each of the 3 scales of processes to assure the early tests can be leveraged for the later ones with sound scientific basis that can be used to support CMC and regulatory submissions as a total package.

Some potential specs might include Dose, Manufacturing Impurities, Degradant levels at batch release, PEG average molecular weight/number and PDI, overall molecular weight and range, ratio of PEG to fatty acid bridges, number of ligands per 'cide and characterizations might include degradation time in vitro, morphological state in solution, etc. There are average values and variation for each of these that must be controlled and shown as consistent across all of the processes to justify leveraging.

Therefore, they needed to make sure they could reliably make consistent product across all processes before starting the first tests to not waste money or time on a false start.

Other tasks resulting in an 18 month timeline from pre-IND to initial Tox testing:

1. My speculation is that it wasn't until the pre-IND meeting that they really knew everything the FDA wanted to see for CMC and characterization. As they said after the pre-IND in March 2012, FDA gave them specific recommendations for FluCide not included in the standard FDA Guidance documents. FDA likely asked for specific assays and tests and testing plans that needed to be developed, validated and executed. And then multiple lots would have had to be made and tested to set representative specs and tolerances.

2. Annual Report (excerpt below) states they intended to build all Tox study materials at the larger-scale new facility, but schedule and resource constraints there forced them to scale up and make in the smaller-scale laboratory facility. And then they didn't have all the equipment. My opinion - by not realizing sooner the new facility wouldn't be done in time, they cost themselves some time to do the lab scale up in existing facilities. But to their credit, they did recover and find a way to get an important portion of the formal Tox studies started (barely) by end of the wide range of their self-imposed deadline.

3. Multiple process optimizations followed by builds to establish reproducibility, capability to specs and consistency in characterizations all take time as well to make sure batches made now for non-GLP are consistent with batches to be made for GLP animal and Human Clinical studies.

Excerpts:

Press Release Oct 7, 2013
The non-GLP safety and toxicology study was begun in late September at KARD Scientific in Massachusetts. The results of this study will provide the basis and focus for the IND-enabling GLP safety and toxicology studies of FluCide that are required for the IND submission to the U.S. FDA.

Annual Report June/Sept 2013
After declaring the injectable FluCide drug candidate in February 2012, we have been focused on taking our technology from the small scale syntheses needed for small animal studies to the large scale syntheses for making large batches of our nanoviricides as would be needed for Safety and Toxicology (“Tox Package” studies) and later for human clinical trials. Because of the significant safety observed during the several animal studies designed to test the effectiveness of FluCide drug candidates in small animals, the scale required for the tox package studies was estimated at kilograms. Originally we had intended to perform kg-scale syntheses only after the new lab and facilities designed for such scale up was available. However, the facility program was significantly behind due to challenges related to resources availability as well as significant challenges posed by the need for designing complex functionality in a limited space while performing renovation of an existing space. We therefore decided to perform the synthesis of FluCide for tox package in our existing small-scale laboratory. We have been optimizing the processes and translating laboratory operations to appropriate chemical process unit operations in the subsequent time frame. This is a very significant undertaking, given the constraints of our current small-scale facility. After we have completed these process optimizations, we will still need to produce at least three to five batches of the injectable FluCide, analyze the product for comparability, and combine these batches to produce a master batch sufficient to perform the tox package studies with. These activities are currently in progress.

While we have made significant progress in this scale up program at our current facility, certain key equipment pieces that we need are still on back order at present with certain vendors. After these equipment pieces arrive, we will need to set them up, validate them and then use them for the operations they are intended for. This continues to be an item causing delays in our goal of making sufficient quantities of FluCide for the tox package study and it is outside of the Company’s control.

Bottom line from my point of view - they met their communicated deadline (even if you think they should have beat that) and are on the right track.